Mutations in the insulin receptor gene are known to be a cause of some rare forms of extreme insulin resistance. The relevance of mutations in the insulin receptor gene as well as other candidate genes in the pathogenesis of the more common aging-related type II diabetes mellitus are currently unknown. Some evidence indicates that one rare form of diabetes mellitus, MODY, is associated with mutations in the glucokinase gene. Likewise mutations in the insulin receptor gene; insulin gene; and in mitochondrial DNA have been associated with rare forms of the disease. Current methods used to screen for mutations in candidate genes (SSCP- DGGE-ASO) are PCR-based and would miss large gene deletions (as well as gene amplifications). For this purpose we have developed a novel PCR-based method, gene dose-PCR (gdPCR), which allows rapid and sensitive screening for gene deletions as well as gene amplifications (Celi et al. Nucleic Acid Res. 1993;21(4):1047, Celi et al. Exp.Clin.Endocrinol. 1993;101(Suppl2):330-332). gd-PCR is extremely versatile and has been successfully used for the prenatal diagnosis of trisomy 21 (Down's syndrome) from amniocytes. We have also screened the tyrosine kinase domain (exons 17,18,19,20 and 21) as well as exons 3,9 and 14 of the insulin receptor gene in five type II diabetic mexican americans finding no deletions. We plan to continue screening for deletions/amplifications with gd-PCR as well as screening with conventional methods such as SSCP for point mutations in the insulin receptor gene of these subjects. We also plan to study other candidate genes such as IRS-I (insulin receptor substrate-1), glucokinase, the other hexokinases, glycogen synthase and the glucose transporters.